This Lung Cancer SPORE application is a new application submitted by the Vanderbilt-Ingram Cancer Center and its affiliated institutions. In this proposal, we apply the translational research strengths of the Vanderbilt-Ingram Cancer Center toward reducing the incidence, morbidity, and mortality of lung cancer, by focusing on the discovery and validation of molecular targets for prevention and therapy. In project 1 we are studying the role of specific matrix metalloproteinases and targeted inhibitors in the development and behavior of lung cancer. In Project 2 we are applying sophisticated cDNA microarray and protein mass spectrometry techniques to the identification of molecular fingerprints of lung cancer. These fingerprints could ultimately be used to guide patient care or discover novel molecular targets for therapy. Project 3 studies a new potential molecular target, Notch3, that we identified by mapping a balanced chromosome translocation. This also represents a completely new mechanism for gene activation in lung cancer. Receptor tyrosine kinase inhibitors are an exciting new class of molecularly targeted reagents, and in Project 4 we study their effects on downstream signaling pathways and their use in combination with radiation therapy in anti-angiogenic tumor therapy. In projects 5 and 6 we investigate the role cyclooxygenase 2 (COX2) in the therapy (Project 5) and prevention (Project 6) of lung cancer. We have unique facilities for the analysis of COX2 metabolites and intend to study eicosanoid production by human lung cancer tumors in situ, its association with tumor angiogenesis, and its response to treatment with specific inhibitors in vivo. For Project 6 we propose to use two cohorts with previously collected pharmacy data to study the impact of long term COX2 inhibitors on the incidence of lung cancer. The first is a retrospective cohort study over 10,000 enrollees of the Tennessee Medicaid Program who were diagnosed with chronic obstructive pulmonary diseases (COPD) during the period of 1980 to 2002. The second is a population-based cohort and nested case-control studies of over 150,000 users of NSAIDs in North Jutland County, Denmark during the period of 1991 to 2002. In order to accomplish these research goals, we propose 4 cores: administrative, tissue, clinical, and biostatistical. The proposed career development and developmental research programs are tightly integrated with established institutional initiatives with documented track records of identifying and funding promising projects and individuals. We will use these established mechanisms to fund lung cancer-targeted career development and research projects. We believe that these projects, cores, and pilot and career development awards could lead to major improvements in the prevention, diagnosis, and treatment of lung cancer.